NAD+ for Healthspan, Long-term Cognition, and Energy

Nicotinamide adenine dinucleotide (NAD+) plays a fundamental role in life and health through the regulation of energy biogenesis, redox homeostasis, cell metabolism, and the arbitration of cell survival via linkages to apoptosis and autophagic pathways. Apart from reducing the functions of mitochondria, biological changes such as cognitive impairments, DNA damage and sirtuin gene inactivation, are brought about by aging which can be evaded by enhancing NAD+ count in the body

 

What is The Cellular Key To Youthful Vitality? - R3 Health

All sirtuins are NAD+ dependent.

 

This Healthline piece suggests that “Research in humans has shown that NMN in doses of up to 1,200 mg daily are safe to consume.” Both Dr. Brad Stanfield and Dr. Rhonda Patrick point out that a possible cancer promotion effect of NR and NMN is dependent on senescent cells. This makes a prior period of autophagy a must if one is to use NR or NMN. The FDA banned NMN, possibly because of this study hinting a cancer promotion. That study, however, has been scathingly criticized by Dr. Brad Standfield.

 

NAD+ plays a pivotal role in the regulation of DNA repair, stress resistance, and cell death. NAD+ precursors have been shown to slow down ageing and extend lifespan in yeasts, and protect severed axons from degeneration in animal models neurodegenerative diseases.

 

Health benefits as a result of implementing approaches to increase NAD+ bioavailability.

 

NAD+ level can be regulated by lifestyle and nutrition approaches such as fasting, caloric restriction, sports activity, low glucose availability, and heat shocks. By implementing healthy lifestyle approaches, endogenous intracellular NAD+ levels can be increased, which explains the molecular mechanisms underlying health benefits at the organismal level. Namely, adherence to here presented healthy lifestyle approaches is correlated with an extended life expectancy free of major chronic diseases.

 

Ageing is accompanied by a gradual decline in tissue and cellular NAD+ levels in multiple model organisms, including rodents and humans. This decline in NAD+ levels is linked causally to numerous ageing-associated diseases, including cognitive decline, cancer, metabolic disease, sarcopenia and frailty. Many of these ageing-associated diseases can be slowed down and even reversed by restoring NAD+ levels. There are substances in foods that do this, as presented here. NMN is found in broccoli, cabbage, cucumber, edamame, tomato, and avocado.

 

NMN and niacin supplementation have the potential to make one feel younger. The benefits include improved, younger looking skin. More than 400 enzymes require NAD. As we age and our NAD levels go down, so does our metabolism decline. Maintaining youthful levels of NAD may help one become more resilient against diseases including COVID-19, causing recovery to happen 3 days faster. Mitochondrial health and muscle strength may benefit. NAD level in older adults who exercise resemble that of younger individuals. There is no evidence though of maximum lifespan extension.

 

This randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial included 80 middle-aged healthy adults being randomized for a 60-day clinical trial with once daily oral dosing of placebo, 300 mg, 600 mg, or 900 mg NMN. NMN supplementation was well tolerated. Walking distance increase during the six-minute walking test was statistically significantly higher in the 300 mg, 600 mg, and 900 mg groups compared to placebo at both days 30 and 60, with longest walking distances measured in the 600 mg and 900 mg groups. The blood biological age increased significantly in the placebo group and stayed unchanged in all NMN-treated groups at day 60, which resulted in a significant difference between the treated groups and placebo.

 

Disease models have also conclusively demonstrated how functional failure is intimately connected to a decline in NAD+ levels in most tissues. For example, renal NAD+ levels are lower in situations of acute kidney injury [] or diabetic nephropathy []. Similarly, reduced cardiac NAD+ levels are found in situations of dilated cardiomyopathy [], ischemia [] or pathological hypertrophy [].

 

Across the kingdom of life, an increase in intracellular levels of NAD+ triggers shifts that enhance survival, including boosting energy production and upregulating cellular repair. In fact, the slow, ineluctable process of aging has been described as a “cascade of robustness breakdown triggered by a decrease in systemic NAD+ biosynthesis and the resultant functional defects in susceptible organs and tissues.” By middle age, our NAD+ levels have plummeted to half that of our youth. Numerous animal studies have demonstrated that boosting NAD+ levels increases insulin sensitivity, reverses mitochondrial dysfunction, and extends lifespan.,

Why NAD+ declines with age

NAD+ is reduced with age at a cellular, tissue, and organismal level due to inflammation, defect in NAMPT-mediated NAD+ biosynthesis, and the PARP-mediated NAD+ depletion. This leads to a decrease in cellular energy production and DNA repair and modifies genomic signalling leading to an increased incidence of chronic diseases and ageing.

 

The NAD+-consuming PARPs, a total of 17 members in mammals, play important roles in DNA repair, and the regulation of transcription and metabolism, among other tasks. In response to age-dependent accumulation of DNA damage, PARPs consume more NAD+ resulting in reduced cellular/tissue NAD+

 

NAD+ declines during ageing due, in part, to increased  CD38 enzyme activity, driven by the accumulation of senescent cells. The age-associated increase of senescent cells in visceral white adipose tissue and liver, characterised by irreversible cell cycle stagnation and the acquisition of a pro-inflammatory senescence-associated secretory phenotype (SASP), enhanced CD38-dependent NADase activity. This blog post on autophagy may help one to minimize senescent cells. Regardless of whether NAD+ is boosted endogenously (via exercise) or via supplements, the CD38 enzyme must be minimized for maximum benefit.  Lipopolysaccharide (LPS), sometimes called endotoxaemia can increase CD38. LPS is covered in this blog post on chronic inflammation.

 

Apigenin, a flavonoid widely distributed in plants (especially parsley and chamomile) is a CD38 inhibitor.

 

it has been shown that NADases can directly regulate autophagy and mitochondrial quality control. Conversely, autophagy has been shown to preserve NAD levels by modulating cellular stress.

 

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Benefits in cardiac function by CD38 suppression: Improvement in NAD+ levels, exercise capacity, heart rate variability and protection against catecholamine-induced ventricular arrhythmias.


 

NAD+ level can be regulated by lifestyle and nutrition approaches such as fasting, caloric restriction, sports activity (exercise), low glucose availability (ketosis or calorie restriction), and heat shocks. NAD+ is reduced with age at a cellular, tissue, and organismal level due to inflammation. Strategies that conserve cellular NAD(+) may reprogram dysfunctional adult stem cells and improve life span in mammals. NAD+ level can take 4-6 weeks to stabilize.

 

In preclinical models of ageing, nutritional insults (high fat–high sucrose diet, alcohol) and various metabolic disorders such as obesity, type 2 diabetes or fatty liver disease, NAD is often severely depleted to levels that impair redox metabolism and reduce the activity of sirtuins.

 

Supplementation of NAD+ precursers (NMN, NR, niacin) improves DNA repair, mitochondrial dysfunction & hearing loss in mice. Nicotinamide adenine dinucleotide (NAD) is a vital metabolic redox co-enzyme found in cells and is necessary for over 500 enzymatic reactions. It plays a crucial role in various biological processes, including metabolism, aging, cell death, DNA repair, and gene expression. Thus, NAD+ is critical for human health and longevity. It should be pointed out, though, the NAD+ precursors have not, or rarely, shown any life extension in mice.


 

Timing is important

 

NMN may be best taken in the morning as a rise in NAD+ late in the day may affect sleep. This study of 30 healthy volunteers received 250 mg/day of NMN (n = 15) or placebo (n = 15) for 12 weeks showed that oral administration of NMN is a safe and practical strategy to boost NAD+ levels in humans. The NAD+ salvage pathway is dependent on SIRT1.  NAMPT and NAD+ levels oscillate during the daily 24-hour cycle and that this oscillation is regulated by the circadian clock. Activation of AMP-activated protein kinase (AMPK) increases SIRT activity by elevating NAD levels. Currently, several studies have shown that NMN, the NAMPT reaction product, is able to be utilised to trigger the SIRT1 activity

 

Hepatic nutrient-sensing mTOR, AMPK or AKT signaling, became rhythmic specifically in obese mice treated with NAD+ raising therapy just before the active phase. Remarkably, NAD+ at the onset of the rest phase was accompanied by uncoupled oscillations between the SCN and the hepatic clock, which were phase inverted in the liver, while keeping behavioral rhythms largely intact. These findings demonstrate that the time of day determines the beneficial effects of NAD+-based therapies.


 

Dr. Jin-Xiong She: NMN can reduce inflammation (CRP), experience more energy, reduce senescence, reduce oxidative stress, reduce triglycerides, reduce liver enzymes. If taken with a program to reduces senescent cells, you can expect a reduction in Beta Genectocytes, which is a biomarker of senescence. Dr. Jin’s personal experience is of an improvement in allergies and asthma. A knee problem and a sciatic nerve problem also disappeared. He can now, at age 61, play tennis without pre-dosing with Tylenol.

 

NMN administration significantly increased blood NAD+ levels in 10 healthy volunteers without damaging blood cells and significantly reduced blood triglyceride (TG) levels.

 

NAD shots are popular, but do not offer long-term benefit.

 

Niacin or Niacamide is an Inexpensive, Available NAD+ Booster

 

Niacin is an efficient NAD+ booster in humans. Niacin boosts muscle mitochondrial biogenesis and respiratory chain activity in humans. This study is discussed here.

A single dose of nicotinamide (niacinamide) at (200 mg) led to the maximal whole blood concentration by a 30-fold increase at 0.5 h with a consistent decrease until 6 h in all 6 healthy male volunteers. NAD+ levels reached a maximum concentration at 12 h.

 

One clinical trial showed that supplementation of 200 mg nicotinamide (niacinamide), a form of vitamin B3, increased blood NAD+ levels. Here we report a clinical trial to assess the efficacy of a lower and a higher dose nicotinamide on increasing NAD+ levels. Blood NAD+ levels were evaluated before and after treatment of 100 mg nicotinamide, 500 mg nicotinamide, or water only. The three treatment arms were tested in the same cohort of 5 healthy adults. Oral supplementation of 500 mg nicotinamide led to a significant increase in blood NAD+ after 12 h and showed a trend of increase after 48 h (P = 0.056), whereas 100 mg nicotinamide or water intake only did not change the NAD+ levels in the same subjects.

 

Tolerance of doses near 1 g (or up to 3 g) of daily intake of NAM, even during long-term administration, has been demonstrated in many studies.

 

Niacin cures systemic NAD+ deficiency and improves muscle performance in adult-onset mitochondrial myopathy.

 

Niacin appears to promote insulin resistance in most, if not all, subjects who take more than a gram daily for weeks at a time. This insulin resistance is initially associated with an increase in fasting glucose due to decreased disposal rates (the speed at which glucose is moved from the blood to tissues), with later increases in fasting insulin levels.


 

How is NAD+ Made? Salvage Pathway

The key to sustained high levels of NAD+ is exercise

 

Aerobic and resistance exercise training reverses age‐dependent decline in NAD+ salvage capacity in human skeletal muscle. Aerobic exercise training increased NAMPT abundance 12% and 28% in young and older individuals, respectively, whereas resistance exercise training increased NAMPT abundance 25% and 30% in young and in older individuals, respectively. Dr. Rhonda Patrick discusses the role of NAD+ recycling and NAMPT here.

 

The level of physical activity correlates positively with the NAD+ abundance detected in muscle biopsies from older humans (Janssens et al., 2022).

 

Nicotinamide adenine dinucleotide (NAD+) was one of the most prominent metabolites that was lower in older adults, in line with preclinical models. This lower level was even more pronounced in impaired older individuals, and conversely, exercise-trained older individuals had NAD+ levels that were more similar to those found in younger individuals. NAD+ abundance positively correlated with average number of steps per day and mitochondrial and muscle functioning.

 

We can actively fight back against age-related decline with resistance training to restore our levels of NAD+, a critical molecule used by the mitochondria in our cells to produce energy.

 

A sedentary lifestyle could be enough to decrease skeletal muscle mitochondrial amounts and, consequently, NAD+ levels, even in the absence of an overt disease state or changes in NAD+ consuming enzymes activities.

 

This study of 16 untrained participants, 59±4 years old, completed 10 weeks of full-body resistance training (2 d/wk) showed that muscle NAD+, NADH, and global SIRT activity are positively affected by resistance training in middle-aged, untrained individuals to the level of college-age participants.

 

Aerobic and resistance exercise training reverses age‐dependent decline in NAD + salvage capacity in human skeletal muscle.

 

In an exercise intervention study, NAMPT protein increased by 127% in sedentary nonobese subjects after 3 wk of exercise training (P < 0.01).

 

Resistance training increased NAMPT abundance by 25% and 30% in young and in older individuals, respectively.

 

Here are various reports of the effect of exercise on NAMPT which is the rate-limiting factor the NAD+ salvage pathway.

 

In skeletal muscle, NAD+ is mainly generated by the NAD+ salvage pathway (illustrated above) in which nicotinamide phosphoribosyltransferase (NAMPT) is rate-limiting. NAMPT decreases with age in human skeletal muscle. Aerobic exercise training increased NAMPT abundance 12% and 28% in young and older (≥55 years) individuals, respectively, whereas resistance exercise training increased NAMPT abundance 25% and 30% in young and in older individuals, respectively.

 

NAD + salvage governs mitochondrial metabolism, invigorating natural killer cell antitumor immunity.

 

Middle-aged, untrained (MA) participants (59±4 years old; n=16) completed 10 weeks of full-body resistance training (2 d/wk).  Data from trained college-aged men (22±3 years old, training age: 6±2 years old; n=15) were also obtained for comparative purposes. Muscle NAD+, NADH, global SIRT activity, and NAMPT protein increased from Pre to Post in MA participants. Additionally, Pre muscle NAD+ and NADH in MA participants were lower than college-aged participants, whereas Post values were similar between cohorts. Interestingly, muscle citrate synthase activity levels (i.e., mitochondrial density) increased in MA participants from Pre to Post, and this increase was significantly associated with increases in muscle NAD+. In summary, muscle NAD+, NADH, and global SIRT activity are positively affected by resistance training in middle-aged, untrained individuals.

 

Chronic inflammation lowers NAMPT and increases CD38. This blog post on chronic inflammation may help.

 


Benefits for the Brain

 

NAD boosters such as nicotinamide riboside may prevent amyloid accumulation in worms and mice that are models of Alzheimer’s disease.

 

Oral gavage of 400 mg/kg NMN successfully increases brain NAD+ levels in mice after 45 min.

 

Oral NR increases brain NAD+ levels in individuals with Parkinson’s disease.

 

Nicotinamide riboside, a naturally occurring dietary supplement, can enter the brain and alter the metabolism of relevant biological pathways involved in neurodegenerative diseases like Alzheimer’s. Perhaps the best way to increase NAD+ in the brain is via exercise.

 

Neural stem/progenitor cells (NSPCs) undergo cell divisions to differentiate into the major cell types of the brain, such as neurons, oligodendrocytes, and astrocytes. Aging is a negative regulator of NSPC proliferation, whereas NSPCs could be reactivated in the aged brain: restoring the function of NSPCs could effectively prevent age-associated cognitive decline. NAMPT-mediated NAD+ biosynthesis was critical for NSPC self-renewal, proliferation, and differentiation into oligodendrocytes. Long-term NMN administration was able to maintain the NSPC pool. NMN administration reduced defects in oligodendrogenesis caused by decrease in NAD+ levels. Thus, NMN could be a promising agent for maintaining the NSPC pool and reactivating NSPCs. NMN was able to induce NSC proliferation (via SIRT1 and SIRT2) and promote NSC differentiation (via SIRT1, SIRT2, and SIRT6).


 

Oxidative stress

Oxidative stress and decreased DNA damage repair in vertebrates increase with age also due to lowered cellular NAD+. NAD+ depletion may play a major role in the aging process at the cellular level by limiting (1) energy production, (2) DNA repair, and (3) genomic signaling.

 

Exogenous NAD+ administration to cells in a petri dish suppresses H2O2-induced oxidative stress and protects retinal pigment epithelium cells against PARP-1 mediated necrotic death through the up-regulation of autophagy. The results suggest that exogenous NAD+ administration might be potential value for the treatment of age-related macular degeneration.

 

The strong positive correlation observed in rats between DNA damage associated NAD+ depletion and Sirt1 activity suggests that adequate NAD+ concentrations may be an important longevity assurance factor.

 

This study of human skin cells showed that NAD+ depletion may play a major role in the aging process, by limiting energy production, DNA repair and genomic signalling.


NAD+ for Healthspan

 

Reduced stem cell function leads to the diminished replenishment of the tissue in essentially all adult stem cell compartments.108,109,110 The lack of efficient repair of these damaged tissues is the consequence of stem cell decline and aging.111,112 The importance of NAD+ for maintaining the pool and pluripotency of stem cells makes it an essential cofactor during aging.

 

250 mg NMN per day to 65 aged men aged 65+ for 6 or 12 weeks in a placebo-controlled, randomized, double-blind, parallel-group trial. Metabolomic analysis of whole blood samples demonstrated that oral NMN supplementation significantly increased the NAD + and NAD + metabolite concentrations. Significant improvement in gait speed and the 30-second chair stand test were observed. This study showed that chronic oral NMN supplementation can be an efficient NAD + booster for preventing aging-related muscle dysfunctions in humans.

 

300 mg was given to post-menopausal women (mean age 55.0 years) . HbA1c in glucose metabolism decreased from 5.34to 5.23 % and HDL-C in lipid metabolism increased from 67.5 to 72.3 mg/dL. T cells increased and skin quality improved.

 

More Energy via NAD+

 

Across the kingdom of life, an increase in intracellular levels of NAD+ triggers shifts that enhance survival, including boosting energy production and upregulating cellular repair. Numerous studies have demonstrated that boosting NAD+ levels increases insulin sensitivity, reverses mitochondrial dysfunction, and extends lifespan.,11

 

Elderly and Exercise | Westbury Total Health Care

 

The ratio of NAD+/NADH indicates the cellular redox state. A decrease in this ratio affects the cellular anaerobic glycolysis and oxidative phosphorylation functions, which reduces the ability of cells to produce ATP. Therefore, increasing the exogenous NAD+ supply under certain disease conditions or in elderly people may be beneficial.

 

NMN

 

Nicotinamide adenine dinucleotide (NAD+) levels in the body deplete with aging and it is associated with down-regulation of energy production in mitochondria, oxidative stress, DNA damage, cognitive impairment and inflammatory conditions. However, NMN, as the precursor of NAD+, can slow down this process by elevating NAD+ levels in the body. NMN is the most effective NAD+ booser, according to Dr. David Sinclair.

 

NMN may activate AMPK, which may be part of it’s youthfulness promotion.

 

Here is a video presentation of all human NMN trials so far.

 

NMN appears to be stable in water; in one study 93%–99% of NMN was maintained intact in drinking water at room temperature for 7–10 days. NMN also appears to be rapidly absorbed. Compared to NR, NMN is already one step further down the pathway to produce NAD+: NR => NMN => NAD+. NMN is better than NR according to Dr. David Sinclair.

 

 A 12-week randomized, double-blind, placebo-controlled, parallel-group clinical trial of 36 healthy middle-aged participants who received one capsule of either 125 mg NMN or placebo twice a day. Among the NAD+ metabolites, the levels of nicotinamide in the serum were significantly higher in the NMN intake group than in the placebo group. Pulse wave velocity values indicating arterial stiffness tended to decrease in the NMN intake group.

 

This 2018 Cell Metabolism paper claims that oral NMN and NR are metabolized in the mouse liver. Unlike in cell culture, where NR and NMN are readily incorporated into NAD, oral administration fails to deliver NR or NMN to tissues without breaking the
nicotinamide-ribose bond. This would render NMN and NR ineffective as oral supplements ???

 

In contrast to the above, this randomized, double-blind placebo-controlled study of humans taking 250 mg NMN in the afternoon appears to significantly improve sleep, reduced drowsiness, and improve some performance of physical tasks. These types of improvements may also impact a person’s day-to-day attitude, which may then improve one’s quality of life and may extend the number of years that they live in overall good health.

 

250 mg NMN per day was given to aged men for 6 or 12 weeks in a placebo-controlled, randomized, double-blind, parallel-group trial. Chronic NMN supplementation was well tolerated and caused no significant deleterious effect. Metabolomic analysis of whole blood samples demonstrated that oral NMN supplementation significantly increased the NAD + and NAD + metabolite concentrations. There were nominally significant improvements in gait speed and performance in the left grip test. Therefore, chronic oral NMN supplementation can be an efficient NAD + booster for preventing aging-related muscle dysfunctions in humans.

 

NMN Helps You Age Better

 

This placebo-controlled, randomized, double blind, parallel-group trial showed that giving 250 mg NMN per day to aged men for 6 or 12 weeks (n=21 for 6 weeks, n=10 for 12 weeks) significantly increased the concentrations of NAD+ and NAD+ metabolites. Moreover, NMN significantly improved muscle strength and performance, which were evaluated using the 30-second chair stand test, walking speed, and grip strength, and it showed no significant effect on body composition.

 

NMN administration to 10 healthy volunteers significantly increased blood NAD+ levels without damaging blood cells and significantly reduced blood triglyceride (TG) levels. These findings imply that intravenous administration of NMN may lead to the prevention and treatment of diseases associated with increased TG levels, such as fatty liver and diabetes.

 

In this study of 25 pre-diabetic women, 250 mg of NMN improved the ability of insulin to increase glucose uptake in skeletal muscle, which often is abnormal in people with obesity, prediabetes or Type 2 diabetes. NMN also improved expression of genes that are involved in muscle structure and remodeling. However, the treatment did not lower blood glucose or blood pressure, improve blood lipid profile, increase insulin sensitivity in the liver, reduce fat in the liver or decrease circulating markers of inflammation as seen in mice.

 

125 mg of NMN twice per day reduced arterial stiffness in this 12-week study of 36 healthy middle-aged participants

 

This study of 80 healthy middle-aged and older adults (40 – 65 years old), both males and females found that blood intracellular NAD levels were found significantly increased in response to 300 mg, 600 mg, and 900 mg NMN oral administration. The study concluded 600 mg daily oral intake is the optimal dose on observation that 900 mg did not give further significant improvement over 600 mg in blood cellular NAD concentration. HOMA-IR values (for insulin sensitivity) were unaffected by NAD+ blood level. There were problems with this study, as pointed out by Dr. Brad Steinfield, though not with the dose vs. blood NAD+ level data.

 

In this study, healthy volunteers received 250 mg/day of NMN (n = 15) or placebo (n = 15) for 12 weeks. No obvious adverse effects were observed. NAD+ levels in whole blood were significantly increased after NMN administration. Dr. Brad Steinfield discusses this study in this video.

 

NMN supplementation leads to significant increase in intracellular NAD+ level, NAD+/ NADH ratio, Sirt3 expression, as well as ameliorated mitochondrial function and rescued senescent mesenchymal stem cells (MSCs). Additionally, Sirt3 over-expression relieved mitochondrial dysfunction, and retrieved senescence-associated phenotypic features in MSCs.

 

NMN has, anecdotally, treated allergies, sinus infections, eyesight, and arthritis as shown in this video.

 

NMN produces significant beneficial effects for those with Parkinson’s disease by attenuating apoptosis and improving energy metabolism in a cellular model of PD. These results suggest that NMN may become a promising therapeutic drug for PD.

 

Most of the NMN studies have been done in mice, often using doses that are excessive by human standards.

 

  • NMN appears to be stable in water; in one study 93%–99% of NMN was maintained intact in drinking water at room temperature for 7–10 days. NMN also appears to be rapidly absorbed.
  • Treatment of mice with the NAD+ precursor nicotinamide mononucleotide (NMN) improves blood flow and increases endurance in elderly mice by promoting SIRT1-dependent increases in capillary density, an effect augmented by exercise or increasing the levels of hydrogen sulfide (H2S), a DR mimetic and regulator of endothelial NAD+ levels. Interestingly, the NMN treatment did not improve blood vessel density and exercise capacity in young sedentary mice. However, it did boost blood vessel formation and exercise capacity in young mice that had been exercising regularly for a month.
  • NMN effectively mitigates age-associated physiological decline in mice. Without any obvious toxicity or deleterious effects, NMN suppressed age-associated body weight gain, enhanced energy metabolism, promoted physical activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies. Consistent with these phenotypes, NMN prevented age-associated gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metabolism and mitonuclear protein imbalance in skeletal muscle. NMN supplementation has no effect in the young mice because they are still making plenty of their own NMN. We suspect that the increase in inflammation that happens with aging reduces the body’s ability to make NMN and, by extension, NAD.”
  • A single dose of NMN, administered to male mice, increased hippocampal mitochondria NAD+ pools for up to 24 hr post-treatment. This reduced hippocampal reactive oxygen species levels via SIRT3-driven deacetylation of mitochondrial manganese superoxide dismutase. Consequently, mitochondria in neurons become less fragmented. Manipulation of mitochondrial NAD+ levels by NMN results in metabolic changes that protect mitochondria against reactive oxygen species and excessive fragmentation.
  • Long-term NMN administration affects metabolism and aging and also conveys the ideas of functional hierarchy and frailty for the regulation of metabolic robustness and aging in mammals.
  • Supplementation of NAD+ and its intermediates through diet has also showed promising results in the protection against systemic decline of tissue form and function, as evidenced by the increased resistance to age-related pathogenesis and promotion of healthy aging in mice. Pioneering studies have demonstrated that NMN treatment ameliorates glucose intolerance and insulin insensitivity in diet-induced diabetic mice. NMN treatment of aged mice can bring about rejuvenation of brain function; in particular, it has been shown to improve spatial working memory function and gait coordination, which could be attributed to sirtuin-mediated neurovascular transcriptomic changes.
  • Of 590 genes differentially expressed in aged mice, 204 of which were restored toward youthful expression levels by NMN treatment. Neurovascular protective effects of NMN are mediated by the induction of genes involved in mitochondrial rejuvenation, anti-inflammatory, and anti-apoptotic pathways.
  • NMN prevented age-associated gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metabolism and mitonuclear protein imbalance in mouse skeletal muscle.
  • Treating mice with a NAD+ precursor, or “booster,” called NMN improved their cells’ ability to repair DNA damage caused by radiation exposure or old age. “The cells of the old mice were indistinguishable from the young mice, after just one week of treatment” said lead author Professor David Sinclair.
  • NMN prevents age-associated gene expression changes in a tissue-specific manner.
  • Feeding mice an NAD+ precursor such as NMN, the telomeres were stabilized. Furthermore, feeding NAD+ precursor to the mice not only maintained telomere length but also improved liver condition in these mice,” Sahin said.
  • Longer telomeres were observed in both the mice and volunteers with NMN supplementation, suggesting the potential of NMN use at a pre-aging phase to retard the proceeding of aging.
  • NMN reverses age-associated decline in exercise capacity by increasing skeletal muscle capillary density in a Sirt1-dependent manner: After two months of NMN feeding, there was a robust improvement in exercise capacity of old mice, where NMN-fed old mice ran two times greater distance compared to other old mice in a treadmill test.
  • NMN rejuvenates bone stem cells in mice.
  • NMN reduces metabolic impairment in male Mouse offspring from obese mothers.
  • In mice, both a high-fat diet and aging compromise NAMPT-mediated NAD biosynthesis, contributing to the pathogenesis of diet- and age-induced type 2 diabetes. 
  • Insulin sensitivity has been increased via NMN. NMN has been shown to be anti-inflammatory in mice
  • NMN supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice.
  • In a mouse Alzheimer model, NMN reduced beta-amyloid accumulation.
  • Long-term NMN administration significantly improves eye function, bone density, and myeloid-lymphoid composition in aged mice.
  • Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice.
  • The decline of NAD+ levels in the heart is accompanied by aging, causing cardiac pathological remodeling and dysfunction. NMN has emerged as a precursor to alleviate age-related cardiac pathophysiological changes by improving cardiac NAD+ homeostasis.
  • This study from a Japanese University which showed that NMN, either injected or oral, enhanced the effectiveness of Natural Killer (NK) cells in their ability to kill cancer cells in mice.
  • NMN treatment blocked UVB-induced photodamage in mice, maintaining normal structure and amount of collagen fibers, normal thickness of epidermis and dermis, reducing the production of mast cells, and maintaining complete organized skin structure. Furthermore, NMN reduced oxidative stress of skin and liver by promoting the activation of the AMP-activated protein kinase (AMPK) signaling pathway and further increasing the expression of downstream antioxidant genes of AMPK.
  • NMN mitigated silicosis-induced lung damage in mice at 7 and 28 days, manifested as a decreasing coefficient of lung weight and histological changes, and alleviated oxidative damage by reducing levels of reactive oxygen species and increasing glutathione. Meanwhile, NMN treatment also reduced the recruitment of inflammatory cells and inflammatory infiltration in lung tissue. Transcriptomic analysis showed that NMN treatment mainly regulated immune response and glutathione metabolism pathways. Additionally, NMN upregulated the expression of antioxidant genes Gstm1Gstm2, and Mgst1 by promoting the expression and nuclear translocation of nuclear factor-erythroid 2 related factor 2 (Nrf2).
  • NMN effectively suppressed aging-induced body weight gain and ameliorated eye dysfunction in mice.
  • NMN supplementation promotes neurovascular rejuvenation in aged mice: transcriptional footprint of SIRT1 activation, mitochondrial protection, anti-inflammatory, and anti-apoptotic effects

 

Here is a video suggesting reasons for the FDA banning NMN.

 

ProHealth Longevity’s Uthever NMN one-kilo or 100 gram powder packs are a good bet on purity. ProHealth NMN is sold on AliExpress at a good price, where one may also side-step the FDA ban.


NR (Nicotinamide Riboside)

250 mg NR was orally administered on Days 1 and 2, then uptitrated to peak dose of 1000 mg twice daily on Days 7 and 8. On the morning of Day 9, subjects completed a 24-hour PK study after receiving 1000 mg NR at t = 0. Significant increases comparing baseline to mean concentrations at steady state were observed for both NR and NAD+; the latter increased by 100%.

 

NR acts as a potent modifier of NAD+ metabolism, muscle mitochondrial biogenesis and stem cell function, gut microbiota, and DNA methylation in humans irrespective of BMI.

 

An alternative pathway for NAD+ synthesis bypassing NAMPT has received considerable attention recently. This pathway uses dietary NR to generate NMN catalyzed by the muscle-specific NRK2 [10,43].

 

Oral NR supplementation (500 mg, 2x /day, 6 weeks) increases NAD+ levels in the brain of 22 healthy older adults. Orally administered NR can augment neuronal NAD+ levels and modify biomarkers related to neurodegenerative pathology in humans.

 

Human studies of NR:

  • NR is not stable in circulation, and its utilization is rate-limited by the expression of nicotinamide riboside kinases. NR is is quickly degraded into vitamin B3. In contrast, NMN is very stable.
  • A 2 × 6-week randomized, double-blind, placebo-controlled, crossover clinical trial that chronic supplementation with the NAD+ precursor vitamin, nicotinamide riboside (NR), is well tolerated and effectively stimulates NAD+ metabolism in healthy middle-aged and older adults. 
  • This randomized, double-blinded, placebo-controlled, crossover intervention study was conducted in 13 healthy overweight or obese men and women found that NR  increased sleeping metabolic rate. But no effects of NR were found on insulin sensitivity, mitochondrial function, hepatic and intramyocellular lipid accumulation, cardiac energy status, cardiac ejection fraction, ambulatory blood pressure, plasma markers of inflammation, or energy metabolism.
  • This 2019 paper says “dietary NR supplementation has no significant impact on skeletal muscle mitochondria in obese and insulin-resistant men”.
  • NR is the main precurser of NAD+ in the central nervous system and the preferred precursor in mitochondria. NAD+ maintains the function of mitochondria by regulating the activity of sirtuin. It has also been shown to exert a certain ameliorating effect on alcohol-induced liver disease and depressive behaviour, and improve diabetic lesions and hepatic steatosis in mice with high-fat diet-induced obesity. NR can ameliorate angiotensin Ⅱ-induced cerebral small vessel disease in mice, and prevent noise-induced hearing loss. Similar to NMN, NR can also improve female fertility. NR has been shown to exert a certain degree of therapeutic effect in the pathological progress of neurodegenerative diseases such as AD, aging, cerebral apoplexy], and hypertension and cardiovascular diseases. Numerous studies have shown that NR can increase the lifespan of all species tested so far, including mice.

Mouse studies of NR:

  • Administration of the NAD precursor NR in mice rapidly ameliorated functional deficits and restored muscle mass, despite having only a modest effect on the intramuscular NAD pool. Additionally, lifelong overexpression of Nampt preserved muscle NAD levels and exercise capacity in aged mice, supporting a critical role for tissue-autonomous NAD homeostasis in maintaining muscle mass and function.
  • NR supplementation in mammalian cells and mouse tissues increases NAD+ levels and activates SIRT1 and SIRT3, culminating in enhanced oxidative metabolism and protection against high-fat diet-induced metabolic abnormalities.
  • Feeding the NAD+ precursor nicotinamide riboside (NR) to aging mice protected them from muscle degeneration. NR treatment enhanced muscle function and also protected mice from the loss of muscle stem cells. The treatment was similarly protective of neural and melanocyte stem cells, which may have contributed to the extended life span of the NR-treated animals.
  • Supplementation with the NAD+ precursor nicotinamide riboside (NR) markedly reprograms metabolic and stress-response pathways that decline with aging through inhibition of the clock repressor PER2. NR enhances BMAL1 chromatin binding genome-wide through PER2K680 deacetylation, which in turn primes PER2 phosphorylation within a domain that controls nuclear transport and stability and that is mutated in human advanced sleep phase syndrome. In old mice, dampened BMAL1 chromatin binding, transcriptional oscillations, mitochondrial respiration rhythms, and late evening activity are restored by NAD+ repletion to youthful levels with NR. NMN probably does the same.
  • NR delays senescence of neural stem cells and melanocyte stem cells and increases mouse life span.
  • NR did not increase lifespan significantly in mice at the doses tested in this study.
  • NAD+ repletion via NR improves mitochondrial and stem cell function and enhances life span in mice.
  • This randomized, placebo-controlled, double-blinded, and parallel-group designed clinical trial of forty healthy, sedentary men with a body mass index (BMI) > 30 kg/m2, age-range 40-70 y showed that 12 wk of NR supplementation in doses of 2000 mg/d appears safe, but does not improve insulin sensitivity and whole-body glucose metabolism in obese, insulin-resistant men.
  • This randomized, double-blind, and placebo-controlled study in a population of 120 healthy adults between the ages of 60 and 80 years found that a combination of nicotinamide riboside and pterostilbene significantly increases the concentration of NAD+ in a dose-dependent manner after 4 weeks.
  • This randomized, double-blind, placebo-controlled, crossover clinical trial of 60 healthy middle-aged and older men and women between the ages of 55 and 79 years showed that chronic supplementation with (500 mg, 2×/day) of nicotinamide riboside is well tolerated and effectively stimulates NAD+ metabolism in healthy middle-aged and older adults.
  • Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults.
  • NAD+ supplementation with NR in the FRDA model of mitochondrial heart disease does not alter SIRT3 activity or improve cardiac function.
  • Myocardial mtDNA damage in combination with high dosages of nicotinamideriboside (NR) causes an inhibition of sirtuin activity due to accumulation of nicotinamide (NAM), in addition to irregular cardiac mitochondrial morphology.
  • Nicotinamide riboside supplementation does not alter whole-body or skeletal muscle metabolic responses to a single bout of endurance exercise.

 


 

Trimethylglycine (TMG) is a useful supplement to take if one uses NMN or niacin. Dr. Brad Standfield explains here.

 

 

 

 

 

 

 

 

 

By Otto

I am a health enthusiast, engineer, and maker.